The long-term goal of this project is to develop replacement gene therapy as a treatment of a dog model of autosomal recessive retinitis pigmentosa (arRP). The dog model to be used in these studies is the only animal model of arRP due to a mutation in the gene encoding the alpha subunit of cyclic GMP phosphodiesterase (PDE6A). Mice models have been used successfully in preliminary trials of therapy eventually intended for the treatment of arRP. However, features of mice eyes including their size, their predominantly rod-mediated nocturnal vision and the difficulty in accurate assessment of vision mean that treatment trials using a larger animal model with eyes that are morphologically and functionally closer to human eyes are required prior to human trials. The dog is currently the only larger animal species that fills that need, as there are naturally occurring retinal dystrophies for which the causal gene mutations have been identified. The proposed studies will utilize a recombinant adeno-associated virus (rAAV) vector systems to introduce a normal copy of PDE6A to the photoreceptors of the PDE6A mutant dog. A lentivirus system that offers a more rapid expression of the transgene will also be investigated in the dog model, initially using a green fluorescent protein reporter gene and then PDE6A for therapeutic trials. Evidence of photoreceptor rescue will be identified by electroretinography, vision testing and detailed retinal histology. The effect that timing of injection at different stages of disease has on extent of rescue will be investigated. A comparison between the rAAV and lentivirus systems will include a comparison of speed of onset of expression, duration of reporter gene expression and effect of repeated subretinal injection of vector to different regions of the fundus.